tbuckley/cabot-search huggingface dataset:
Abstract 2625: Personalized chemotherapy treatments for microsatellite instable tumors
Authors: Adam Hoffman, Sanjima Pal, Veena Sangwan, Lorenzo Ferri
Journal: Cancer Research (2022)

Abstract Introduction: Esophagogastric adenocarcinomas with microsatellite instability (MSI) high status often display chemoresistance, as the current therapies are ineffective. It is hypothesized that the poor response of MSI-high esophagogastric adenocarcinomas to therapies is due to the extensive genomic mutational heterogeneity, which can be overcome by identifying, stratifying, and targeting multiple genetic alterations concurrently. The goals of this project are to: 1) Identify a matched retrospective cohort of 20 MSI-high to 20 microsatellite stable organoids, derived from biobanked tumor tissue. 2) Analyze mismatch repair protein function/loss, to confirm that the primary tumor microsatellite status is recapitulated in 3D organoid models. 3) Test standard of care chemotherapies, and explore alternative approaches to prevent chemoresistance by evaluating targeted agents based on genomic sequencing. Methods: Patient-derived organoids grow for ~14 days, after which they are enzymatically disrupted and plated in Matrigel. I will confirm that the organoid models accurately represent clinal response, by treating them with the same chemotherapy received by the patient. 10 different drug concentrations are added in triplicate using a drug dispenser, then after 72 hours, organoid viability is determined with a plate reader. Results: Genomic characterization of 13/226 MSI-high cases has been conducted with a 234 gene gastric cancer specific panel to identify and target genomic alterations. Preliminary robotic drug screens guided by these mutation profiles have been conducted, yielding promising alternative treatments. Conclusions: By targeting the particular mutations found in MSI-high patients, it could help explain the chemoresistance mechanism, so promising personalized treatment approaches for esophagogastric adenocarcinomas can be clinically implemented. Sources of Funding: This project is funded by the Inez and Willena Beaton Award in Oncology, valued at $7,500 and provided by the RI-MUHC. The operating grants that support the research are $120,000 over 2 years from the Cancer Research Society, and $1,200,000 USD over 3 years given by the Department of Defense. Citation Format: Adam Hoffman, Sanjima Pal, Veena Sangwan, Lorenzo Ferri. Personalized chemotherapy treatments for microsatellite instable tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2625.
Abstract 3848: Neuronal mimicry promotes breast cancer leptomeningeal metastasis from bone marrow
Authors: Andrew E. Whiteley, Trevor T. Price, Brennan G. Simon, Katie R. Xu, Dorothy A. Sipkins
Journal: Cancer Research (2022)

Abstract Breast cancer cell (BCC) metastasis to the leptomeninges (LM) is an increasingly common disease complication with a grim prognosis of weeks to months. There are currently few therapeutic options to prevent or treat leptomeningeal disease (LMD), in part due to our limited knowledge of the molecular pathways involved in tumor invasion and survival within this unique niche. Here we show that BCCs in mice can bypass the restrictive blood-brain barrier and invade the LM by migrating along the abluminal surface of emissary vessels that connect the vertebral/calvarial bone marrow and meninges. This is mediated by tumor cell integrin α6 engaging extracellular matrix laminin on the vascular basement membrane. Upon invasion of the LM, BCCs co-localize with CSF1R+ meningeal macrophages/microglia in the perivascular space. We demonstrate that ablation of these myeloid cells by CSF1R inhibition leads to prolonged disease-free survival due to decreased LMD burden. Importantly, we show that CSF1R+ cell depletion does not prevent tumor cell LM colonization, but instead limits disease expansion within the LM, highlighting the pro-tumor phenotype of these meningeal macrophages/microglia. Our data suggest that meningeal macrophages/microglia support BCC proliferation/survival by up-regulating glial cell line-derived neurotrophic factor (GDNF), a key neurotrophic factor released by macrophages/microglia in response to neuronal injury. In vitro, GDNF protects BCCs from cell death induced by glucose deprivation, suggesting that tumor cells may hijack a macrophage neuronal injury response program to thrive within the nutrient-poor LM niche. Unexpectedly, we found that integrin α6 deletion or antibody blockade eliminates the protective role of GDNF by modulating GDNF/NCAM receptor signaling in BCCs. Taken together, our data suggest that BCCs co-opt neuronal pathfinding mechanisms and resident macrophages/glia to efficiently invade and thrive within the LM niche. Integrin α6 appears to be a master regulator of this neuronal mimicry through its ability to promote abluminal vessel trafficking and mediate responsiveness to GDNF. Finally, a case-control study of bone-metastatic breast cancer patients reveals a significant correlation between integrin α6 expression and incidence of dural-based meningeal metastasis, suggesting the clinical relevance of this pathway and potential role of α6 integrin as a biomarker of LMD risk and therapeutic target. Citation Format: Andrew E. Whiteley, Trevor T. Price, Brennan G. Simon, Katie R. Xu, Dorothy A. Sipkins. Neuronal mimicry promotes breast cancer leptomeningeal metastasis from bone marrow [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3848.
Abstract 5104: Extracellular vesicles expressing CEACAM proteins in the urine of bladder cancer patients
Authors: Ko Igami, Takeshi Uchiumi, Masaki Shiota, Saori Ueda, Masatoshi Eto, Dongchon Kang
Journal: Cancer Research (2022)

Abstract Purpose: Early detection and long-term monitoring are important for urothelial carcinoma of the bladder (UCB). Urine cytology and existing markers have insufficient diagnostic performance. Here, we used medium-sized extracellular vesicles (EVs) in urine to find specific markers for UCB and evaluate their usefulness as diagnostic material. Experimental Design: To search for specific markers in urinary EVs derived from UCB, we performed a comparative analysis using shotgun proteomics with urine from four UCB patients and four healthy subjects. Next, we used male 24 healthy specimens, 18 non-cancer specimens, and 29 UCB specimens for analysis of urinary EVs using a flow cytometer to evaluate the diagnostic performance of UCB-specific EVs. Results. NTA analysis showed that the size of EVs extracted from urine by centrifugation was mostly less than 400 nm. By shotgun analysis of EVs, we detected several proteins characteristic of UCB and found that CEACAM proteins was increased in patients. Flow cytometric analysis revealed that the degree of expression of CEACAM1, 5, and 6 antigens on the surface of EVs varied among patients. EVs expressing CEACAM antigens also expressed MUC1, suggesting that they were derived from tumorigenic uroepithelial cells. The number of EVs expressing CEACAM1, 5, and 6 proteins (CEACAMs+EVs) was significantly increased in UCB (Mean9.5%±SD14%), non-bladder cancer (0.69±0.46), and healthy (0.37±0.31) by flow cytometry. The results of ROC analysis showed a good score of AUC=0.929. A provisional CEACAMs+EVs cutoff % was established with a sensitivity of 83% and specificity of 98%. Here, seven out of nine cases of negative urine cytology (class 2) were determined to be positive. Conclusions: The presence of CEA antigen in the urine of patients with bladder cancer is known, but it has not yet been practically used for diagnosis. We have discovered EVs that specifically express these antigens and have obtained useful diagnostic performance. EVs expressing CEACAM proteins in urine are expecting target as a new liquid biopsy for UCB patients. Citation Format: Ko Igami, Takeshi Uchiumi, Masaki Shiota, Saori Ueda, Masatoshi Eto, Dongchon Kang. Extracellular vesicles expressing CEACAM proteins in the urine of bladder cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5104.
Abstract 5806: Mieap forms membraneless organelles to compartmentalize and facilitate cardiolipin metabolism
Authors: Naoki Ikari, Yasuyuki Nakamura, Hirofumi Arakawa
Journal: Cancer Research (2022)

Abstract Liquid droplets function as membraneless organelles that compartmentalize and facilitate efficient biological reactions. They are formed by proteins with intrinsically disordered regions (IDRs) via liquid-liquid phase separation. Mieap/SPATA18, a p53-inducible protein, participates in suppression of colorectal tumors by promoting mitochondrial quality control. However, the regulatory mechanism involved remains unclear. Here, we report that Mieap is an IDR-containing protein that drives formation of liquid droplets in mitochondria. Mieap liquid droplets specifically phase separate the mitochondrial phospholipid, cardiolipin. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions involved in cardiolipin metabolism, including biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1, and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap liquid droplets. Mieap-deficient mice exhibit altered crista structure in mitochondria of various tissues, including brown fat, and tend to become obese. These results suggest that Mieap drives formation of membraneless organelles to compartmentalize and promote cardiolipin metabolism at the inner mitochondrial membrane, thus potentially contributing to mitochondrial quality control. Citation Format: Naoki Ikari, Yasuyuki Nakamura, Hirofumi Arakawa. Mieap forms membraneless organelles to compartmentalize and facilitate cardiolipin metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5806.
Abstract 1898: SNAF: Accurate and compatible computational framework for identifying splicing derived neoantigens
Authors: Guangyuan Li, Nathan Salomonis
Journal: Cancer Research (2022)

Abstract Patient outcome with immune checkpoint blockade (ICB) therapy relies largely on the presence and detection of tumor neoantigens. Neoantigens can be produced from a broad spectrum of genetic (SNV, fusion) and non-genetic (splicing, alternative promoter) sources. While alternative splicing is a broad source of neoantigens, concerns regarding their tumor specificity have hindered their evaluation as therapeutic targets relative to SNVs. To systematically define tumor-specific and likely immunogenic neoantigens, we developed SNAF (Splicing Neo Antigen Finder), an easy-to-use and open-source computational workflow. SNAF automates the prediction of high-confidence patient-specific and shared splicing derived neoantigens from RNA-Seq data. This workflow leveraged deep learning and hierarchical Bayesian models to prioritize potential splicing-neoantigen candidates by their tumor specificity (inferred off-target effects) and immunogenicity (T cell reactivity). SNAF is compatible with all major splicing identification algorithms and can be easily integrated into any existing splicing analysis workflows. SNAF predicted splicing neoantigens were validated with an improved accuracy over alternative approaches in ovarian cancer HLA targeted MS profiles. Applied to 825 breast cancer patients in TCGA, we find that splicing neoantigens are frequently shared among patients and overall burden is highly associated with overall survival and specific clinical subtypes. These data suggest alternative genomic monitoring of splice-derived neoantigen burden can be used to prioritize selection of patients for ICB. Citation Format: Guangyuan Li, Nathan Salomonis. SNAF: Accurate and compatible computational framework for identifying splicing derived neoantigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1898.
Abstract 2653: Synthetic, small molecule glycosaminoglycan mimetics induce novel anti-cancer activity through preferential targeting of a growth factor receptor
Authors: Connor O'Hara, Shravan Morla, Ravikumar Ongolu, Nirmita Patel, Rio Boothello, Bhaumik Patel, Umesh Desai
Journal: Cancer Research (2022)

Abstract Glycosaminoglycans (GAGs), such as heparan sulfate (HS), have been implicated in tumor initiation, progression and metastasis. Earlier we have shown that a defined GAG sequence of six residues, but not four or eight residues, inhibits colorectal cancer stem cells (CSCs) by inducing activation of p38 MAPK. To transform this sequence into a drug-like molecule, we developed a synthetic mimetic of the GAG sequence, labeled as G2.2, which was also found to selectively target CSCs over bulk adherent tumor cells. Unfortunately, G2.2’s oral bioavailability was low. To improve upon its drug-like properties, we pursued a hypothesis-driven analog design to derive three lipid-modified analogs (LMAs). Across a panel of &amp;gt; 15 patient-derived colorectal cancer (CRC) cell lines, which could be stratified according to their clinically-relevant consensus molecular subtypes, LMAs showed enhanced potency while retaining selectivity against CSCs in spheroid inhibition assays. Both G2.2 and LMAs displayed better inhibition of cell lines with mesenchymal phenotypes and metabolic dysregulation. Microarray-based screening against more than a dozen receptor tyrosine kinases led to identification of IGF1R as a potential receptor of the synthetic GAG mimetics. To ascertain these screening results, biophysical studies were performed to clarify preferred soluble and/or cell surface target receptors. In line with microarray results, G2.2 preferentially bound to IGF1R in comparison to its soluble ligand IGF-1. G2.2 also preferred IGF1R as compared to an alternative receptor FGFR1. Further, LMAs bound to IGF1R with improved affinities as compared to parent mimetic G2.2, which could explain anti-CSC inhibition results. Unexpectedly, detailed fluorescence titrations revealed that IGF1R affinity of LMAs is minimally impacted by salt concentration, suggesting that these GAG mimetics utilize non-ionic forces in binding, which support the selectivity of target engagement. Overall, this work proves a powerful proof of concept that synthetic GAG mimetics, such as G2.2 and LMAs, present a unique class of anti-cancer therapeutics with high potential for selective elimination of the tumor initiating subpopulation of CRC cells in patient tumors. Citation Format: Connor O'Hara, Shravan Morla, Ravikumar Ongolu, Nirmita Patel, Rio Boothello, Bhaumik Patel, Umesh Desai. Synthetic, small molecule glycosaminoglycan mimetics induce novel anti-cancer activity through preferential targeting of a growth factor receptor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2653.
Abstract 5741: Characterizing isoform switching events in esophageal adenocarcinoma
Authors: Yun Zhang, Katherine M. Weh, Connor L. Howard, Jean-Jack Riethoven, Jennifer L. Clarke, Kiran H. Lagisetty, Jules Lin, Rishindra M. Reddy, Andrew C. Chang, David G. Beer, Laura A. Kresty
Journal: Cancer Research (2022)

Abstract Esophageal adenocarcinoma (EAC), the major subtype of esophageal cancer in the US, is characterized by increasing incidence rates and high mortality due to ineffective screening, late-stage diagnosis, and poor treatment efficacy. The only known precursor to EAC is Barrett’s Esophagus (BE), but the precise mechanisms and molecular events leading to disease progression are still being unraveled. In recent years, analysis of TCGA data revealed that isoform switching events with predicted functional consequences are common in many cancers, but the characterization of switching events in esophageal adenocarcinoma (EAC) is lacking. Next-generation sequencing was utilized to detect levels of RNA transcripts and specific isoforms in 66 treatment naïve esophageal tissues from 41 patients. Tissues ranged from premalignant Barrett’s esophagus (BE), BE with low or high-grade dysplasia (LGD or HGD) to EAC. Samples were stratified by histopathology, p53 mutation status, and significant isoform switching events with predicted functional consequences, followed by enrichment analysis. Barrett’s with high-grade dysplasia increased risk for EAC progression. Comparing BE with LGD and BE with HGD, isoform switching events were identified in 75 genes including KRAS, APC, RNF-128 and WRAP53. Stratification based on p53 status increased the number of significant isoform switches to 135 suggesting switching events impact cellular functions based on tissue histopathology, as well as p53 status. Analysis of isoforms agnostic to mutant p53, exclusive to mutant p53, and shared between the two groups revealed unique signatures including demethylation, lipid and retinoic acid metabolism, and glucuronidation, respectively. About 25% of isoform switching events were identified without significant alteration of gene-level expression. Importantly, two p53-interacting isoforms, RNF128 and WRAP53, were significantly linked to patient survival. Analysis of global isoform switching consequences and alternative splicing events also revealed significant changes in the fraction of coding transcripts, complete open-reading-frames, signal peptides, alternative 5’ donor sites, and alternative transcription start sites. Thus, analysis of isoform switching events may provide new insight for the identification of prognostic markers and inform new potential therapeutic targets for EAC treatment or prevention. Citation Format: Yun Zhang, Katherine M. Weh, Connor L. Howard, Jean-Jack Riethoven, Jennifer L. Clarke, Kiran H. Lagisetty, Jules Lin, Rishindra M. Reddy, Andrew C. Chang, David G. Beer, Laura A. Kresty. Characterizing isoform switching events in esophageal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5741.
Abstract 1443: Environmental heavy metal toxicity and mammographic breast density in a Mississippi Delta southern state
Authors: Bobbie Dean Fine, Shelbie Stahr, Lora J. Rogers, Gail A. Runnells, Tung-Chin Chiang, Lihchyun J. Su
Journal: Cancer Research (2022)

Abstract Importance: Increased mammographic density (MD) is a strong independent risk factor for breast carcinoma. Ubiquitous environmental heavy metal (HM) exposure/toxicity appears pro-carcinogenic in several human cancers. However, studies in the current scientific literature have not elucidated specific connections between HM exposure and mammographically detected increases in breast density. Objective: To determine whether increases in heavy metals (ie, chromium, arsenic and cadmium) measured in urine as a biomarker for long-term exposure, associate with increased MD in a female study cohort in Arkansas. Design, Setting, Participants: One hundred thirty-nine participants in the Arkansas Rural Community Health (ARCH) study cohort, recruited through a mobile mammography unit at baseline, were included in this pilot study. Demographic/health history questionnaire data, urine, blood and saliva samples and incident mammograms classified by BI-RADS were ascertained after informed consent. Study protocol was approved by the Institutional Review Board at the University of Arkansas for Medical Sciences (UAMS). Main Outcome and Measures: Urinary chromium, arsenic and cadmium levels were determined using inductively coupled plasma mass spectrometry. The concentrations of HM were adjusted for urinary creatinine and specific gravity and the results categorized into tertiles. Multivariable logistic regression models were used to evaluate the association between HM exposure and MD. Association of both continuous and categorical variables were examined. Confounding variables in the multivariable models including age, race, BMI, age at menarche and smoking history were determined by a priori knowledge and statistical assessment. Results: Odds ratios (OR) and 95% confidence intervals (CI) for the association between each tertile of HM exposure and MD were used for the assessment. For the unadjusted model, increasing ORs for MD were noted with increased levels of both Chromium and Arsenic exposure. Increased ORs for MD were observed with increased levels of Chromium, Arsenic and Cadmium exposure in the multivariable adjusted model. However, none of these associations demonstrated statistical significance in this limited pilot study. Conclusion: Positive associations between HM exposure and MD were noted after adjusting for age, sex, BMI, age at menarche and smoking history in this pilot study. However, the association did not reach statistical significance at α = 0.05. Citation Format: Bobbie Dean Fine, Shelbie Stahr, Lora J. Rogers, Gail A. Runnells, Tung-Chin Chiang, Lihchyun J. Su. Environmental heavy metal toxicity and mammographic breast density in a Mississippi Delta southern state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1443.